The present invention relates to viscous formulations and to methods for treating and/or preventing various peripheral diseases and conditions by peripheral administration to a patient of a viscous formulation. Peripheral administration includes intradermal, subdermal, subcutaneous, intramuscular, intra-articular (i.e. to treat an articular pathology such as a knee or facet joint osteoarthritis) and epidural (i.e. to treat a radiculopathy, spondylitis, and spondylosis [also known as degenerative disc disease, spinal arthritis, osteoarthritis of the spine]) routes of administration. The administration can be carried out, for example, by injection, insertion or implantation of the viscous formulation. In particular the present invention relates to extended release and sustained release viscous formulations, including injectable implants, for treating various non-ophthalmic inflammatory and/or painful conditions, such as skin or joint pain and/or inflammation, radicular pain from nerve root irritation or inflammation, or chronic back pain from spondylosis or spondylitis.
A pharmaceutical composition (synonymously a formulation or a composition) is a formulation which contains at least one active ingredient (for example an anti-inflammatory polymer such as a polymeric hyaluronic acid and/or a corticosteroid such as a triamcinolone) as well as, for example, one or more excipients, buffers, carriers, stabilizers, preservatives and/or bulking agents, and is suitable for administration to a patient to achieve a desired effect or result. The pharmaceutical compositions disclosed herein can have diagnostic, therapeutic, cosmetic and/or research utility in various species, such as for example in human patients or subjects.
Therapeutic use of a hyaluronic acid or of a corticosteroid is known. Thus, hyaluronic acid (also called hyaluronan and sodium hyaluronate) formulations for both therapeutic and cosmetic use are known. Hyaluronic acid is most frequently referred to as hyaluronan due to the fact that it exists in vivo as a polyanion and not in the protonated acid form. U.S. Pat. Nos. 4,636,524; 4,713,448; 5,099,013, and 5,143,724 disclose particular hyaluronans or hyaluronic acids and methods for making them. Additionally, intra-articular use of a hyaluronic acid (i.e. as a viscosupplement) or of an anti-inflammatory steroid is known. See e.g. Kopp S. et al., The short-term effect of intra-articular injections of sodium hyaluronate and corticosteroid on temporomandibular joint pain and dysfunction, J Oral Maxillofac Surg 1985 June; 43(6):429-35; Grecomoro G., et al., Intra-articular treatment with sodium hyaluronate in gonarthrosis: a controlled clinical trial versus placebo, Pharmatherapeutica. 1987; 5(2):137-41; Adams M., An analysis of clinical studies of the use of crosslinked hyaluronan, hylan, in the treatment of osteoarthritis, J Rheumatol Suppl. 1993 August; 39:16-8, and; Jones, A. et al., Intra-articular hyaluronic acid compared to intra-articular triamcinolone hexacetonide in inflammatory knee osteoarthritis, Osteoarthritis Cartilage. 1995 December; 3(4):269-73
Commercially available hyaluronic acid formulations include Juvederm™ (Allergan), an injectable dermal filler comprised of a cross-linked hyaluronic acid. Also known are Orthovisc® (Anika), Durolane (Smith & Nephew), Hyalgan® (Sanofi), Hylastan® (Genzyme), Supartz® (Seikagaku/Smith & Nephew)), Synvisc® (Genzyme), Euflexxa®, (Ferring) which are used as injectable (intra-articular) hyaluronic acid viscosupplements, of various molecular weights with various degrees of cross-linking of the hyaluronic acid, for treating osteoarthritis joint pain.
Compositions for therapeutic or cosmetic use comprising a high molecular weight hyaluronic acid and one or more active agents has been disclosed. See e.g. U.S. patent application Ser. Nos. 11/039,192; 11/695,527; 11/742,350; 10/966,764; 11/354,415, and; 11/741,366.
Certain corticosteroids (such as triamcinolone) can have anti-inflammatory properties. Thus, intra-articular corticosteroids have been used to treat various joint diseases. See e.g. Zulian F., et al., Triamcinolone acetonide and hexacetonide intra-articular treatment of symmetrical joints in juvenile idiopathic arthritis: a double-blind trial, Rheum 2004; 43:1288-1291. (use of 2 mg to 80 mg of triamcinolone acetonide) and; Hertzberger-ten Cate R. et al., Intra-articular steroids in pauciarticular juvenile chronic arthritis, type I, Eur J Ped 1991; 150: 170-172 (intra-articular 20 mg triamcinolone used to treat juvenile arthritis). Triamcinolone has been used to treat joint stiffness (Clark D. et al., The influence of triamcinolone acetonide on joint stiffness in the rat, J Bone Joint Surg Am 1971; 53:1409-144).
Additionally, intramuscular steroids have been given to treat acute conditions, until the patient can be managed by use of oral steroids, such as asthma (Mancinelli L. et al., Intramuscular high-dose triamcinolone acetonide in the treatment of severe chronic asthma, West J Med November 1997:167(5); 322-329 [up to 360 mg of the triamcinolone was administered daily for three days to a patient]). Subcutaneous and intradermal administration of a steroid is not a preferred route of administration because dermal atrophy can result. When administered by intramuscular injection the risk of dermal atrophy by the steroid can be reduced by giving the injection in a deep gluteal muscle area and avoiding leakage of the steroid formulation into the dermis.
Unfortunately, there are significant drawbacks and deficiencies with known viscous formulations and with known corticosteroid formulations for peripheral use. For example, multiple (five or more) peripheral administrations of a hyaluronic acid can be required to treat a peripheral condition. Additionally, an aqueous corticosteroid formulation of triamcinolone can quickly clear (diffuse out of and/or is removed by one or more active transport mechanisms) from the site of peripheral administration. Rapid clearance can necessitate frequent re-administration (re-dosing) in order to provide an effective treatment. Additionally, therapeutic corticosteroids due to their low water solubility are typically administered as an aqueous suspension of relatively large, irregularly shaped crystals (particles). Such steroid particles can induce an inflammatory response upon administration. This may occur because macrophages present at the administration site can be unable to remove the steroid particles (by phagocytosis) which have a large morphology and irregular geometry. Indeed such particles can be toxic to macrophages and lead to cell death. The death of macrophages then leads to release of pro-inflammatory cytokines that cause both acute and chronic inflammation. Clinical examples of toxicity from particles include gouty arthritis, where urate crystals that range from 5 to 20 microns can cause arthritis. See eg. Helliwell P, Use of an objective measure of articular stiffness to record changes in finger joints after intra-articular injection of corticosteroid, Ann Rheum Dis 1997; 56: 71-73 (intra-articular corticosteroid injection can cause crystal synovitis).
Thus, it is known that macrophages are injured when phagocytosing urate crystals leading to an inflammatory response. Notably, patients treated with medication that reduces macrophage activity, such as colchicine, have a dramatic improvement in their arthritis. Another clinical example of joint deposition of large, irregularly shaped crystals that are injurious to macrophages is pseudo-gout. Here, joint inflammation is caused by deposition of calcium pyrophosphate dehydrate in patients that have hyperparathyroidism. An example of joint inflammation related to injected drug particles is crystal-induced synovitis, where 1-2% of patients that receive intra-articular injections of Lederspan, Kenalog, or other corticosteroid depot formulations, develop a post-injection exacerbation of the joint inflammation. (McCarty D., et al., Inflammatory reaction after intrasynovial injection of microcrystalline adrenocorticosteroid esters, Arthritis and Rheumatism, 7(4); 359-367 (1964) (intra-articular injection of corticosteroids crystals can cause sterile inflammation also referred to as post-injection flare). See also Selvi E. et al., Arthritis induced by corticosteroid crystals, J Rheumatology 2004; 31: 3 (osteoarthritis patient treated with intra-articular injection of 40 mg triamcinolone hexacetonide developed acute arthritis induced by the injected triamcinolone crystals). The particles in these formulations, which are on the average over 10 microns and have irregular morphology, are very similar to the urate crystals in joint of patients with gout or pseudo-gout.
A triamcinolone pharmaceutical composition available under the trade name Kenalog® (Bristol-Myers-Squibb, Princeton N.J.) has been used to treat various conditions by intramuscular or intra-articular (intrabursal use) administration. Each milliliter (ml) of Kenalog® 40 composition comprises 40 milligrams (mg) of triamcinolone acetonide, sodium chloride as a tonicity agent, 10 mg (0.99%) benzyl alcohol as a preservative, 7.5 mg (0.75%) of carboxymethylcellulose sodium and 0.4 mg (0.04%) of polysorbate 80 as resuspension aids. Benzyl alcohol preservative and/or polysorbate 80 can potentially be toxic to sensitive tissues. Thus, preservative-containing corticosteroid formulations have been linked to cases of adhesive arachnoiditis following epidural injections exacerbating a patient's back pain. See e.g. Hurst, E. W., Adhesive Arachnoiditis and Vascular Blockage caused by Detergents and Other Chemical Irritants: an Experimental Study. J. Path. Bact., 1955. 70: p. 167; DeLand, F. H., Intrathecal toxicity studies with benzyl alcohol. Toxicol Appl Pharmacol, 1973. 25(2): p. 153, and; Hetherington, N. J. and M. J. Dooley, Potential for patient harm from intrathecal administration of preserved solutions. Med J Aust, 2000. 173(3): p. 141.
Significantly, the triamcinolone acetonide in Kenalog® rapidly separates and precipitates from the remainder of the formulation. For example, if Kenalog® is left standing for as short a time as about five to ten minutes a substantial separation of a triamcinolone acetonide precipitate from the remainder of the composition occurs. Unfortunately, such rapid settling of the triamcinolone also occurs with other known saline based suspensions of triamcinolone (with or with preservatives and stabilizers). A substantially uniform suspension (which is not provided by Kenalog or other saline based suspensions of triamcinolone) would be beneficial to provide a consistent and accurate dose upon administration of the suspension. In addition, resuspension processing requires the use of the resuspension aids noted above which can affect sensitive tissues.
Additionally, administration of known formulations of a corticosteroid, such as triamcinolone can also result in an allergic or inflammatory reaction possibly due to the burst or high release rates of triamcinolone from the known formulations. As noted above such a reaction can also be due to or be exacerbated due to the large and irregular size of the insoluble corticosteroid particles administered.
Thus, there is a need for a formulation for peripheral administration to treat a peripheral condition which will not have the undesirable characteristics of: presence of toxic preservatives or surfactants in the formulation; rapid release of most or all of the active agent, and that will have a longer period of residence of the active agent at the site of peripheral administration and well as comprising a non or low immunogenic formulation.